european urology 53 (2008) 1138–1150

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Review – Bladder Cancer

Photodynamic Diagnosis in Urology: State-of-the-Art

Dieter Jocham a,*, Herbert Stepp b, Raphaela Waidelich c

a
Department of Urology, University of Lübeck, Lübeck, Germany
b
Laser Research Laboratory, LIFE-Centre, University of Munich, Munich, Germany
c
Department of Urology, University of Munich, Munich, Germany

Article info Abstract

Article history: Objectives: To provide an overview on the methodology and clinical

Accepted November 28, 2007 relevance of fluorescence diagnosis with exogenous fluorochromes or
Published online ahead of fluorochrome prodrugs in urology.
print on December 21, 2007 Methods: The methodology is summarised on the basis of our experience
and the relevant literature. Clinical results and perspectives are reported
Keywords: and concluded after we scanned and evaluated sources from PubMed.
5-Aminolevulinic acid Search items were ‘‘aminolev*’’ or ‘‘hypericin’’ or ‘‘photodyn*’’ or ‘‘por-
Bladder cancer phyrin’’ or ‘‘fluorescence’’ or ‘‘autofluorescence’’ and ‘‘bladder’’ or ‘‘pros-
Hexaminolevulinate tate’’ or ‘‘kidney’’ or ‘‘peni*’’ or ‘‘condylo*’’. Some literature was also
Kidney tumour obtained from journals not indexed.
Penile carcinoma Results: A large number of clinical trials have shown that photodynamic
Photodynamic diagnosis diagnosis (PDD) improves the ability to detect inconspicuous urothelial
Prostate cancer carcinoma of the bladder. Fluorescence diagnosis has recently been
approved in Europe for the detection of bladder cancer after instillation
of a hexaminolevulinate (Hexvix1) solution. PDD is recommended by the
European Association of Urology for the diagnosis of carcinoma in situ of
the bladder. To date, the major weakness of PDD for the detection of
Please visit bladder cancer is its relatively low specificity. Initial results with PDD for
www.eu-acme.org/ the detection of penile carcinoma, prostate cancer, kidney tumours, and
europeanurology to read and urethral condylomata are promising.
answer questions on-line. Conclusions: To determine the actual impact of PDD on recurrence and
The EU-ACME credits will progression rates of bladder cancer, further long-term observational
then be attributed studies are necessary. These studies also will clarify whether PDD is
automatically. cost efficient.
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, University of Lübeck,

Ratzeburger Allee 160, D-23538 Lübeck, Germany. Tel. +49 451 500 2271; Fax: +49 451 500 3388.
E-mail address: Prof.Jocham.MUL@t-online.de (D. Jocham).

0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.11.048
 european urology 53 (2008) 1138–1150
1. Introduction
Photodynamic diagnosis (PDD) involves fluores-
cence to localise abnormal tissue. Therefore, this
procedure is also referred to as fluorescence
diagnosis or fluorescence photodetection. Repre-
senting an additional optical recognition criterion,
PDD reveals neoplastic lesions that cannot be seen
by means of conventional methods. The value
added depends on the selective accumulation
of fluorochrome and on how well interfering
optical tissue inhomogeneities can be considered
or eliminated.
In urology, clinical interest in PDD mainly has
focussed on the improved detection of hardly visible
urothelial bladder cancer. Small papillary tumours
and flat urothelial lesions can easily be overlooked
during conventional white light cystoscopy [1].
Preventing correct and early treatment, missed
diagnosis of high-grade flat lesions such as carci-
nomas in situ (CIS) has a decisive impact on case
outcome. In addition, incomplete resection results
in ‘‘recurrences,’’ that is, merely previously unde-
tected tumours.
Within recent years, PDD of bladder cancer has
found its way into widespread clinical use. The first
exogenous fluorochrome, hexaminolevulinate, has
obtained approval for the detection of bladder
cancer in 26 European countries. According to the
2006 European Association of Urology (EAU) guide-
lines, PDD has been accepted as a method to reveal
areas in the bladder that are suspicious of CIS or of
developing papillary tumour that cannot be seen
with white light cystoscopy. Nevertheless, ‘‘this
investigational method has not yet been implemen-
ted on a regular basis in daily practice’’ (EAU
guidelines on TaT1 [non–muscular-invasive] blad-
der cancer, 2006).
To examine the current status of PDD in urology,
this review summarises development, methodol-
ogy, and clinical experience with special emphasis
on fluorescence diagnosis of bladder cancer.
2. Physics behind PDD
Fluorescence is caused by the interaction of light
(photons) with the outer electrons of molecules.
Molecules that are electronically excited by absorp-
tion of a photon of appropriate wavelength have
several possibilities to return to their ground state.
One option is to emit a secondary photon. Molecules
making use of this relaxation path efficiently are
called fluorochromes. Fluorochromes absorb light
with a high energy per photon and re-emit light with
1139
a lower energy per photon, producing a shift in
colour between excitation and fluorescence light.
Optical filters can block backscattered excitation
light and transmit selectively within the wavelength
bands of fluorescence emission. This is a well-
known procedure used in fluorescence microscopy.
Fluorescent markers, bound to antibodies or intra-
cellularly synthesised, can be detected with high
sensitivity because the unspecific background light
is weak. Thus, these are the advantageous features
of fluorescence detection: lack of background signal
and specific targeting.
Specific targeting for medical diagnostic purposes
implies a contrast in fluorescence of diseased versus
normal tissue. This might be achieved with endo-
genous tissue fluorochromes (autofluorescence) or
by delivering substances that cause specific fluor-
escence staining.
3. Autofluorescence
Among the most efficient endogenous fluoro-
chromes are collagen, elastin, nicotinamide adenine
dinucleotide, flavin adenine dinucleotide, lipofus-
cin, tryptophan, and keratin. Some of these
fluorochromes are located in the subepithelial
connective tissue layer of the corresponding tissue.
The intensity of the perceptible autofluorescence is
thus partly determined by the thickness of the
epithelial cell layer covering connective tissue.
Increased proliferative activity of malignant cells
thereby results in reduced autofluorescence.
Attempts to exclusively exploit endogenous fluor-
escence for tumour recognition have been made
[2,3] and have gained some clinical acceptance with
regards to the detection of early-stage bronchial
cancer.
Early clinical studies have shown that autofluor-
escence may be a promising additional tool to
discriminate neoplastic from benign lesions of the
bladder and penis [2,4]. To date, this diagnostic
method has not found its way into the routine
practice of urologists.
4. Exogenous drugs for fluorescence
The application of exogenous drugs for fluorescence
diagnosis relies on a positive fluorescence staining
of malignant or premalignant tissue. Most of the
substances that already were applied in the clinic
environment are photosensitisers. Apart from
showing fluorescence, photosensitisers also exert
a phototoxic action, which is used for photodynamic
1140 european urology 53 (2008) 1138–1150

therapy (PDT). A recent review, dealing with PDT in autofluorescence, whereas suspicious tissue is
urology, is given by Pinthus et al [5]. PDT will not be identified by its red colour (Fig. 1).
explicitly included in this article, but readers may
keep in mind this additional potential of the 4.1. ALA and derivatives
fluorochromes discussed. Clinical experience in
the use of fluorescence diagnosis in urology has Among the substances available for porphyrin-
been reported for tetracycline, hypericin, and the based fluorescence imaging, 5-ALA is the most
porphyrin-related substances hematoporphyrin widely used. It is a small molecule containing five
derivative, Photofrin1, 5-aminolevulinic acid (5- carbon atoms, a zwitterion with an amino group on
ALA) and, most recently and successfully, its hexyl the one and a carboxylic acid group on the other end.
ester hexaminolevulinate (Hexvix1). For tetracy-
cline fluorescence excitation, UV excitation is
necessary and corresponding instruments were
developed in the early 1960s [6], but UV cystoscopy
was abandoned in the 1970s. Hypericin and por-
phyrins can efficiently be excited by visible violet
light (ca. 400 nm) and emit red fluorescence (590–
700 nm).
Detection of fluorescence signals from tissue is,
unfortunately, not as straightforward as in fluores-
cence microscopy. Excitation light incident on a
tissue surface penetrates several tissue layers where
it is multiply scattered and absorbed from inhomo-
geneously distributed absorbers, mainly haemoglo-
bin. The same is true for fluorescence light excited
somewhere inside the tissue. It is, therefore, not
astonishing that the detectable fluorescence inten-
sity from an endogenous or exogenous fluoro-
chrome is not a reliable quantitative measure of
its local concentration. Additionally, in most clinical
situations, the investigated tissue is excited inho-
mogeneously and from an arbitrary distance and
angle. By applying different wavelengths for excita-
tion or detection and establishing appropriate
algorithms, several groups have tried to generate
more reliable fluorescence signals for diagnostic
fluorescence imaging [7,8].
The currently used clinical instrumentation,
available from several manufacturers of endoscopes
and light sources, is especially designed for fluor-
escence cystoscopy and displays red porphyrin
fluorescence together with blue remitted light.
The blue light serves as a reference. It corrects
inhomogeneous illumination and distance varia-
tions. It also largely compensates for varying blood
absorption and observation angles [9]. The wave-
length of the blue reference light is chosen in a way
to experience intermediate absorption in tissue
Fig. 1 – Fluorescence (a) and white light (b) endoscopic
compared to the high absorption at the excitation
image of a flat pTaG1 lesion adjacent to a small papillary
wavelength and low absorption at the emission tumour that was classified pTaG1 as well. Fluorescence
wavelength. The identification of suspicious tissue staining was performed by instillation of 50 ml of a
by fluorescence occurs quite intuitively by the solution containing 1.5 g 5-aminolevulinic acid.
colour contrast of red fluorescence versus blue Reproduced by permission of the Royal Society of
reference light. Normal tissue thus appears blue Chemistry (RSC) on behalf of the European Society for
with a more or less greenish hue, originating from Photobiology [13].
 european urology 53 (2008) 1138–1150
It plays a natural role in the intracellular biochem-
ical pathways as a heme precursor.
The administration of exogenous 5-ALA bypasses
the rate-limiting step in the biosynthesis of heme,
the synthesis of endogenous 5-ALA in the mito-
chondria. It thereby forces each enzyme in the
pathway to produce its product with maximum
available capacity. The critical bottleneck is the step
from protoporphyrin IX (PpIX) to heme, the insertion
of a ferrous ion into the porphyrin ring, catalysed by
the enzyme ferrochelatase. Thus, exogenously
applied 5-ALA can induce significant intracellular
levels of PpIX. PpIX is an effective photosensitiser
and the only fluorescent substance in the pathway.
The transient accumulation of excess PpIX
preferentially occurs in neoplastic or highly prolif-
erating cells [10]. Among the causes of this phenom-
enon, reduced activity of ferrochelatase and a
relative enhancement of porphobilinogen deami-
nase activity are considered to be the decisive
factors [11,12]. Thus, it is possible to use 5-ALA–
induced fluorescence to locate malignant and
premalignant lesions.
5-ALA can be administered topically in cream or
gel formulations, as an aerosol for inhalation, or as
an instillation liquid as well as systemically, pre-
ferentially by oral delivery. A comprehensive over-
view of the basic principles and clinical applications
of 5-ALA is given in the book by Pottier et al [13].
One of the drawbacks of 5-ALA–based PDD is the
relatively fast photobleaching of PpIX. During
irradiation with fluorescence excitation light, the
photosensitiser PpIX can itself be a victim of the
aggressive oxygen generated. It is then destroyed
and lost for further ‘‘photodynamic purpose’’ (fluor-
escence or phototoxicity). To prevent practical
limitations, instrumentation must be highly sensi-
tive for fluorescence detection and unnecessary
light exposure must be avoided.
Another drawback of 5-ALA is its low lipophilicity,
preventing thorough tissue penetration. With the
aim of enhancing lipophilicity, ester derivatives
have been synthesised. For use in dermatology, the
methyl derivative gained approval (Metvix1, Photo-
cure ASA, Oslo, Norway), whereas for bladder cancer
detection the hexylester hexaminolevulinate (Hex-
vix, GE Healthcare, London, United Kingdom) proved
to be superior. Following intravesical application,
hexaminolevulinate has shown deeper penetration
into the urothelium and production of a higher PpIX
concentration at significantly lower prodrug con-
centrations compared to 5-ALA [14]. The ester
derivatives of 5-ALA cross the cell membrane rather
by passive diffusion in contrast to the parent
compound, which is transported intracellularly by
1141
active uptake via b-amino acid, g-aminobutyric acid
or PEPT1 and PEPT2 membrane transport proteins
[15]. Passive diffusion, in this case, leads to a
considerably faster and more efficient uptake.
Nonspecific esterases in the cells are believed to
at least partly release the parent compound to enter
the heme biosynthesis pathway. It can, however,
not be excluded that the enzymes also may act on
the esters directly, finally producing esterified PpIX.
For this reason, the fluorochromes synthesised on
delivery of hexaminolevulinate are usually referred
to more generally as ‘‘photoactive porphyrins’’
(PAPs). Unlike 5-ALA, hexaminolevulinate is not
suitable for systemic application.
4.2. Hypericin
Hypericin, a hydroxylated phenantroperylenequi-
none, is one of the ingredients that causes the
phototoxic effects of the Hypericum perforatum L
plant (St John’s wort) [16]. Hypericin fluorescence
can be excited and detected with the same equip-
ment as used for porphyrin fluorescence. A con-
siderable practical advantage of hypericin over
porphyrins is its significantly reduced photobleach-
ing, allowing for longer investigation times. Pure
hypericin, which is synthetically produced nowa-
days, is characterised by a number of drawbacks,
such as low solubility, costly production, and to
some extent lack of stability in solution [16]. In vitro
studies have shown that methanolic extracts from
the H. perforatum plant may offer less expensive
alternatives [17]. Solubility could successfully be
increased by nontoxic additives, such as pyrroli-
dones [18].
5. History of applying fluorescence diagnosis
in urology
First attempts with tetracycline fluorescence were
performed in 1957 [19]. In 1975, the haematopor-
phyrin derivative (HpD) was initially proposed for
bladder cancer detection by Kelly [20]. Photofrin1,
a drug derived from HpD, was first applied for
bladder cancer imaging by Baumgartner et al in 1987
[7], after Jocham et al, Nseyo et al, and Dougherty
had published early works on PDT of bladder cancer
with Photofrin in 1985 [21–23].
The main drawback associated with these syn-
thetic porphyrins, at least for exclusively diagnostic
application, is a prolonged skin photosensitisation.
Low-dose drug regimes, which overcome this side-
effect [24,25], necessitate complicated instrumenta-
tion [25].
1142 european urology 53 (2008) 1138–1150

Following publication of first reports on the
clinical suitability of the 5-ALA porphyrin pro-
drug by Kennedy et al in 1990 [26], topical
application of 5-ALA as an intravesically adminis-
tered solution was first implemented clinically by
Kriegmair et al in 1992 [27]. Because the fluores-
cence intensity obtained was much brighter than
with low-dose Photofrin, instrumentation could be
simplified.
6. Fluorescence diagnosis of bladder cancer
6.1. Equipment
Some manufacturers of endoscopes and light
sources offer equipment for fluorescence cysto-
scopy, comprising
 Light source: high-power endoscopic light source
with integrated excitation filter, providing excita-
tion light in the range of 380–470 nm. The light
source can be switched between white light and
fluorescence modes and communicates with the
camera controller.
 Light guide: special light guide for efficient
excitation light coupling to cystoscope.
 Cystoscope: including optimised fibre bundles for
illumination and observation filter in the eyepiece
(alternatively, filter is inserted in the camera
optics). Rigid and flexible versions are available.
Video endoscopes suitable for fluorescence ima-
ging are in development.
 Camera: high-sensitivity version of the
endoscopic camera, including a special ‘‘fluor-
escence mode’’ with preset gain values and
corresponding communication with the light
source.
Although the equipment looks similar to stan-
dard cystoscopy equipment, each of the compo-
nents is specialised and care must be taken to not
mix fluorescence equipment with standard compo-
nents.
In fluorescence mode, brightness is a limiting
factor because fluorescence efficiency of the fluor-
ochromes amounts to only a few percent. Thus, the
quality of the video images is somewhat reduced
compared to white light video, or motion artefacts
have to be considered due to frame integration.
Additionally, old lamps and light guides should
readily be replaced. The surgeon should also provide
for clear irrigation liquid and maintain sufficiently
close distance to the bladder wall.
Urine shows bright green fluorescence, which
results in blurring when in fluorescence mode, if the
bladder was not accurately voided prior to cysto-
scopy.
Porphyrin fluorescence is quite efficiently
bleached during light exposure, especially with
excitation light, thereby contributing to limiting
the observation time. Hypericin fluorescence is
stable under practical conditions of fluorescence
cystoscopy.
6.2. Clinical studies
A large number of clinical trials have shown that
PDD improves detection of bladder cancer (Table 1).
In the published studies, the sensitivity of fluores-
cence cystoscopy is consistently superior to white
light cystoscopy. The mean value of the sensitivities

Table 1 – PDD of urothelial carcinoma of the bladder versus WLC: sensitivity and specificity

Author, year of publication No. of patients Agent Sensitivity, % Specificity, %

PDD WLC PDD WLC

Kriegmair, 1996 [73] 104 ALA 96.9 72.7 66.6 68.5

Koenig, 1999 [52] 55 ALA 87 84 59 —
Riedl, 1999 [74] 52 ALA 94.6 76 43 —
Filbeck, 1999 [75] 120 ALA 96 67.5 35 66.4
Zaak, 2002 [76] 713 ALA 97 — 65 —
Grimbergen, 2003 [42] 160 ALA 97 69 49 78
Hungerhuber, 2007 [77] 875 ALA 92 76.3 41.4 —
Jichlinski, 2003 [78] 52 HAL 96 73 43 43
D’Hallewin, 2000 [48] 40 (CIS) Hypericin 93 — 98.5 —
D’Hallewin, 2002 [79] 87 Hypericin 94 — 95 —
Sim, 2005 [50] 41 Hypericin 82 62 91 98

The em dash indicates missing data.

PDD = photodynamic diagnosis; WLC = white light cystoscopy; ALA = 5-aminolevulinic acid; HAL = hexaminolevulinate; CIS = carcinoma in
situ.
 european urology 53 (2008) 1138–1150
Table 2 – PDD using 5-ALA versus WLC: residual tumour rate at second-look TUR
Author, year of publication No. of patients
Riedl, 2001 [36] 102
Kriegmair, 2002 [35] 129
Filbeck, 2002 [34] 191
Alken, 2007 [29] 604
The em dash indicates missing data.
PDD = following photodynamic diagnosis; WLC = following white light cystoscopy; TUR = transurethral resection.
for fluorescence cystoscopy is 93% (range: 82–97%),
compared to 73% (range: 62–84%) for white light
cystoscopy. Tritschler et al showed the sensitivity of
PDD to be higher than the sensitivity of the urine
marker NMP221BladderChek1 test, voided cytology,
and washing cytology, respectively [28].
Until now, five prospective multicentre studies
comparing fluorescence-guided transurethral resec-
tion (TUR) and conventional TUR using white light
cystoscopy have been published [29–33]. Three of
these trials [29,31,32] were randomised, whereas the
remaining two studies [30,33] focussed on inter-
patient comparison. All five studies showed that
PDD is more effective than white light cystoscopy for
detecting malignant bladder lesions, in particular
CIS. As a consequence of the improved detection
rate, 17% of patients in the study managed by
Jocham received more appropriate treatment fol-
lowing fluorescence-guided cystoscopy [32].
The completeness of resection using PDD has
been studied and three of the four controlled, phase
3 studies proved that the number of tumours
detected at second-look TUR is significantly reduced
in patients following fluorescence-guided cysto-
scopy [29,34–36] (Table 2).
With regard to the recurrence rate, the presented
studies have conflicting results. Three of five studies
have shown that fluorescence-guided TUR
enhances the recurrence-free survival rate after 24
mo (recurrence-free survival rate following PDD
versus white light cystoscopy: 40–88% vs. 28–64%,
respectively) [37–39]. Two studies recently presented
at the congresses of the EAU and the American
Table 3 – PDD using 5-ALA versus conventional WLC: long-term follow-up
Author No. of patients available Recurrence-free survival rate, %
for efficacy analysis
PDD
Daniltchenko [39] 102 41
Denzinger [37] 191 71
PDD = following photodynamic diagnosis; WLC = following white light cystoscopy.
1143
Residual tumour rate, % p
PDD WLC
16 39 0.005
32.7 53.1 0.031
4.5 25.2 <0.001
29 29.2 —
Urological Association [29,40], however, did not
reveal any difference in recurrence rates. Possibly
biasing the evaluation of PDD as a diagnostic tool,
these trials have included topical recurrence pro-
phylaxis. Publications interpreting the data are not
yet available.
Until now, results of two large prospective,
randomised trials on long-term benefit of 5-ALA–
induced fluorescence diagnosis versus white light
cystoscopy have been published [37,39] (Table 3).
Follow-up in these studies was 5 and 8 yr, respec-
tively. Both studies conclude that fluorescence-
assisted TUR increases recurrence-free survival of
patients suffering from non–muscle-invasive
urothelial carcinomas of the bladder.
In the published clinical trials, the selection
criterion for patient inclusion was suspected or
suspected or known urothelial carcinoma of the
bladder. As far as data are available, both patients
with primary and recurrent bladder cancer were
included in all studies. The reported proportion of
patients with primary cancer varied between 32%
[30] and 82% [37].
To date, the major weakness of PDD for the
detection of bladder cancer is its relatively low
specificity. The specificity of fluorescence-guided
cystoscopy reported in comparative studies is not
better or even lower than the specificity of standard
white light cystoscopy (Table 1). In the study
published by Tritschler et al, the specificity of PDD
is even lower than the specificity of voided urine
cytology [28]. False-positive fluorescence may be
induced by inflammation [41] or recent intravesical
Median follow-up, mo
WLC PDD WLC
25 42 39
45 86 83
1144 european urology 53 (2008) 1138–1150
therapy [42]. In addition, normal mucosa may
contain a minimal amount of endogenous PpIX.
Viewed with an acute angle, the thin normal mucosa
represents a thick layer for the observer and may
thus cause the impression of fluorescence. This
preferentially occurs when investigating the bladder
neck, trigone, or diverticula [43].
Whether fluorescence of histologically proven
benign lesions is caused by early malignant genetic
alterations is still the object of research. Molecular
analyses indicate that at least some of the false-
positive hyperplastic urothelial lesions may have to
be considered tumour precursors missed by conven-
tional cystoscopy [44]. Immunohistochemical stain-
ing for p53 and p16, however, did not show a
difference between false-positive fluorescent lesions
and benign lesions [43].
Two clinical studies compared the technical
equipment. These studies indicate that PDD using
rigid cystoscopes results in a higher tumour detec-
tion rate than using flexible cystoscopes (85–94% vs.
70–89%, [45,46]).
Prospective randomised trials that compare the
efficacy of the different exogenously applied fluor-
ochromes for PDD of urothelial carcinomas are still
lacking. A study comparing hexaminolevulinate and
5-ALA for the detection of bladder cancer specified
the derivative to be superior by showing higher
tumour selectivity, lower efficient concentration,
shorter administration time needed and deeper
tissue penetration obtained [47]. Evidence indicates
that specificity of hypericin is superior to specificity
of 5-ALA and hexaminolevulinate [48–50].
6.3. Guidelines and recommendations
Due to the superior sensitivity of this diagnostic
modality, PDD is recommended by the EAU as well
as the Austrian Association of Urology. According to
the EAU guidelines, fluorescence cystoscopy should
be considered for the diagnosis of CIS of the bladder
(grade B recommendation; EAU guidelines [51]). The
consensus board of the Austrian Association of
Urology recommends performing fluorescence-
guided cystoscopy in patients with cytology results
suspicious of urothelial carcinomas but normal
findings in white light cystoscopy and in follow-
up cystoscopy for high-risk urothelial carcinomas,
especially for CIS.
6.4. Side-effects
All studies concurrently available showed that PDD
of bladder cancer using exogenous drugs for fluor-
escence diagnosis is well tolerated [31–33,50,52].
Following intravesical instillation, 5-ALA, hexamino-
levulinate, and hypericin are absorbed systemically
in very low concentration only [53–55]. Therefore, the
side-effects of PDD are mainly limited to local
symptoms such as dysuria, haematuria, bladder
pain, and bladder spasm [32]. With regard to these
symptoms, there is no difference between patients
undergoing fluorescence endoscopy and white light
cystoscopy [35]. The recently reported case of
anaphylactic shock 5 h after intravesical exposure
to hexaminolevulinate, however, clearly necessitates
further assessment [56].
6.5. Fluorescence cytology
Initial investigations have been made with fluores-
cence microscopy. In a standard setting (405–435 nm
excitation, detection with long-pass filters at
approximately 460 nm), porphyrin-containing cells
show red fluorescence, whereas unstained cells are
identified by their weak green autofluorescence. Red
blood cells appear as small dark spots.
In an attempt to simplify the analysis of bladder
washing specimens, a special instrument was
designed to spectrally resolve porphyrin fluores-
cence [57].
Preliminary results with ex vivo fluorescence
cytology using 5-ALA or hypericin and flow cyto-
metry using hexaminolevulinate suggest that this
diagnostic modality may be a useful adjunct to
conventional urinary cytology in detecting malig-
nant urothelial cells [57–59].
7. Fluorescence diagnosis of non-urothelial
tumours
Because the principle of tumour-selective fluores-
cence upon delivery of 5-ALA is not restricted to
bladder cancer, it was investigated for other urologic
applications, too. Urethral condylomata acuminata
detection was first reported by Schneede et al [60],
after Fehr et al and Ross et al had shown selective
staining of such lesions on the vulva and the shaft of
the penis [61,62]. Fluorescence diagnosis of the
urethra is performed 1 h after urethral instillation
of 0.1% solution of 5-ALA. In a single-institution trial,
fluorescence urethroscopy detected additional sub-
clinical human papilloma virus (HPV) lesions in 13 of
43 men [60]. A study of neodymium:yttrium-alumi-
num-garnet (Nd:YAG) laser coagulation of urethral
condylomata following conventional white light
urethroscopy alone and white light endoscopy in
addition to fluorescence urethroscopy after topical
application of 5-ALA showed fewer recurrences in
 european urology 53 (2008) 1138–1150
the fluorescence-controlled group (21.3% vs. 47.3%)
[63].
Early clinical experience indicates that fluores-
cence-guided Nd:YAG laser therapy using topically
applied 5-ALA assists in better discriminating the
tumour margin, thus resulting in more reliable
destruction of all neoplastic tissue in penile-sparing
surgery [4]. Because, following the oral administra-
tion of 5-ALA, PpIX is also accumulated in tumour-
bearing lymph nodes of patients with penile carci-
nomas, PDD may also provide a useful adjunct to
localise metastatic disease in lymphadenectomy [64].
Fluorescence diagnosis of renal cell carcinoma was
first reported by Popken et al in 1999 [65]. In a clinical
pilot study, 5-ALA had been applied systemically
4–6 h prior to organ-preserving tumour resection. In
eight of nine renal tumours, resection borders could
be clearly demarcated by PpIX fluorescence. Despite
these promising results, no further clinical experi-
ence with PDD of kidney cancer has been reported to
date. Because surrounding tissue precludes fluores-
cent photodetection, PDD of renal cell carcinoma is
limited to peripheral tumours.
Applicability for diagnosis and treatment of
prostate carcinomas is a matter of ongoing clinical
studies. First cases were already reported by
Zaak et al in 2003 [66]. Fluorescence microscopy of
cryosections obtained from cancer-bearing pros-
tates after radical surgery showed highly selective
PpIX accumulation in cancer epithelium versus
normal glandular epithelium and connective tissue.
8. Future perspectives
Instrumentation for fluorescence diagnosis will
follow the general trend towards improved resolution
(high-definition TV-standard cameras, video endo-
scopy). The development of semiconductor-based
light sources for fluorescence excitation in combina-
tion with video endoscopy may provide a user-
friendly equipment. Digital image processing on
fluorescence images and overlay on intermittently
acquired white light images may further improve
diagnostic accuracy [67,68]. Especially for systems
used in an outpatient environment, a ‘‘quality check
feature’’ is important to avoid false diagnosis due to
improperly working equipment. The major task will
be to enhance the specificity of PDD.
9. Discussion and conclusions
PDD of bladder cancer has entered the era of
prospective randomised trials. First results of
1145
long-term follow-up studies are available. Unan-
imously, all studies report that fluorescence cysto-
scopy significantly improves the endoscopic
detection of bladder cancer as compared to standard
white light cystoscopy. The enhanced diagnosis of
the sometimes hardly visible CIS by PDD is one of the
most remarkable benefits of this method and
improves management of patients suffering from
this disease. Multivariate analyses have shown that
presence of CIS is an independent unfavourable
prognostic factor, increasing the risk of progression.
Particularly bacillus Calmette-Guérin failures need
meticulous follow-up and individualised therapy
[69]. Therefore, fluorescence cystoscopy should be
considered particularly for the diagnosis of CIS of
the bladder and in follow-up cystoscopy for high-
risk urothelial carcinomas. The high sensitivity of
PDD makes it feasible to refrain from taking random
biopsies or TUR, if there is no suspicious fluores-
cence in PDD.
Patients with multifocal stage Ta bladder
tumours also profit from PDD. Tumour ‘‘recurrence’’
may be due to the persistence of residual tumour in
the bladder after an incomplete TUR or a lesion that
has been overlooked during first endoscopy [70]. The
more complete first resection under PDD control can
make a second-look resection in patients with Ta
bladder tumours unnecessary. Because 5-ALA and
hexaminolevulinate do not penetrate much deeper
than 1 mm, however, fluorescence cannot indicate
invasion depth. Therefore, a second transurethral
resection is indicated in T1 tumours to rule out
muscle invasion.
The adequacy of the TUR also has an important
impact on the percentage of patients with super-
ficial bladder cancer having a recurrence at first
follow-up cystoscopy after initial TUR [70]. It has
been shown that the recurrence at any site in the
bladder at the first follow-up cystoscopy after TUR is
one of the most important prognostic factors for
time to progression [70–72]. Therefore, PDD might
be most advantageous for patients with primary
tumours. Large and multicentre studies, however,
comparing the outcome of patients with primary
and recurrent cancer following PDD are still
warranted.
To determine the actual impact of PDD on
recurrence and progression rates, further long-
term observational studies are necessary. These
studies also will clarify whether PDD is cost
efficient.
Promising initial results with PDD for the detec-
tion of penile carcinoma, prostate cancer, kidney
tumours, and urethral condylomata justify further
clinical studies.
1146 european urology 53 (2008) 1138–1150
Conflicts of interest
The authors have nothing to disclose.
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Editorial Comment on: Photodynamic Diagnosis
in Urology: State-of-the-Art
Marko Babjuk
Department of Urology, General Teaching Hospital,
Charles University, Praha, Czech Republic
marko.babjuk@lf1.cuni.cz
Early cancer detection is an essential prerequisite
of successful therapy. Despite an effort in many
organ locations the principles of photodynamic
diagnosis (PDD) have been applied mostly in bladder
cancer. There is no doubt that fluorescence cysto-
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417–25.
scopy using 5-aminolevulinic acid or hexylester
hexaminolevulinate improves the detection of
bladder cancer as is thoroughly summarized by
Jocham et al [1]. Its efficacy was observed in different
clinical situations and using both rigid and flexible
endoscopes [1]. There is, thus, no surprise that PDD
is routinely used in an increasing number of centers.
However, many aspects remain that must be
considered to be able to exploit the method entirely:
1. Although some smaller prospective randomized
trials showed its positive impact on recurrence
 european urology 53 (2008) 1138–1150
rate in non–muscle-invasive tumors, no infor-
mation is available about progression and
survival rates. In fact, the major benefit of the
method is expected in aggressive tumors where
the aspects of progression and survival must be
considered. The results of prospective random-
ized multicenter trials based on clearly defined
end points and patient population are absolutely
required.
2. The cost efficiency of PDD used in individual
situations along with initial detection, transur-
ethral resection, or follow-up cystoscopy must
be determined. This will help us specify its
indications and incorporate it precisely in
currently used schedules of bladder cancer
management.
3. The biologic background of the method is not
completely understood. The explanation of prin-
ciples of selective accumulation of protopor-
phyrin IX in tumor cells, of laser-induced
autofluorescence, and of interactions between
light and tissue are necessary to use the method
Editorial Comment on: Photodynamic Diagnosis
in Urology: State-of-the-Art
Jehonathan H. Pinthus
Department of Surgery, Division of Urology,
McMaster University, Hamilton, ON, Canada
Jehonathan.Pinthus@hrcc.on.ca
The ultimate goal in the management of super-
ficial bladder cancer is the prevention of disease
recurrence and progression. Recent advances in
photodynamic diagnosis (PDD) render this cur-
rently underused diagnostic technique an addi-
tional important tool in achieving this goal. Many
of the recurrent superficial bladder cancers are
probably undetected tumors that were not initially
resected rather than recurrent new lesions. Con-
sequently, it is reasonable to state that fluores-
cence-guided cystoscopy has significantly higher
tumor detection rates than standard surveillance
cystoscopy and that this can be translated to better
patient care [1]. It seems, however, that the main
obstacle in adopting PDD to routine urologic
practice is the general lack of familiarity with it.
The comprehensive review of Jocham et al clearly
assists in easing this task [2]. It should be
emphasized that, though efficient in reducing
recurrence rates of superficial bladder cancer
1149
totally and improve its specificity [2]. Together
with development of new technologies we could
expect more sophisticated detection tools that
can overcome the user dependence of currently
used techniques and even offer the possibility of
real-time assessment of tissue pathology in vivo
[3].
References
[1] Jocham D, Stepp H, Waidelich R. Photodynamic diagno-
sis in urology: state-of-the-art. Eur Urol 2008;53:1138–50.
[2] Zaak D, Stepp H, Baumgartner R, et al. Ultraviolet-
excited (308nm) autofluorescence for bladder cancer
detection. Urology 2002;60:1029–33.
[3] D’Hallewin M-A, Khatib SE, Leroux A, et al. Endoscopic
confocal fluorescence microscopy in normal and tumor
bearing rat bladder. J Urol 2005;174:736–40.
DOI: 10.1016/j.eururo.2007.11.049
DOI of original article: 10.1016/j.eururo.2007.11.048
and allowing better detection of carcinoma in situ
(CIS), the impact of PDD on the progression of these
tumors remains to be determined. Another caveat
of PPD of urothelial bladder carcinoma is its
relatively low specificity. Although this may
impede its use for diagnostic purposes in patients
who undergo their first work-up for hematuria, it is
not the case for patients with high-risk urothelial
cancer (eg, patients with previous CIS or multifocal
or large Ta bladder cancers). Although not pub-
lished yet, PDD can be potentially very useful in the
investigation of positive urine cytology in the
absence of evident disease in white light cysto-
scopy and normal upper tracts.
In the current era of organ-sparing approaches
in surgical uro-oncology, PDD can be an exciting
potential adjunctive tool. Accordingly, the man-
agement of penile cancer can be complemented by
PDD, specifically in defining the true margins of
the lesion in penile-sparing surgery [3]. Similarly,
preliminary promising results were demonstrated
for partial nephrectomy of peripherally located
kidney cancers [4]. Whether PDD can be used
for the intraoperative detection of positive mar-
gins at the time of radical prostatectomy for
prostate cancer or even in those selected cases
of prostate-sparing radical cystectomy for bladder
1150 european urology 53 (2008) 1138–1150
cancer remains to be determined in specially
designed clinical trials.
References
[1] Filbeck T, Pichlmeier U, Knuechel R, Wieland WF, Roess-
ler W. Clinically relevant improvement of recurrence-
free survival with 5-aminolevulinic acid induced fluor-
escence diagnosis in patients with superficial bladder
tumors. J Urol 2002;168:67–71.
[2] Jocham D. Photodynamic diagnosis in urology: state-
of-the-art. Eur Urol 2008;53:1138–50.
[3] Frimberger D, Schneede P, Hungerhuber E, et al. Auto-
fluorescence and 5-aminolevulinic acid induced fluores-
cence diagnosis of penile carcinoma—new techniques to
monitor Nd:YAG laser therapy. Urol Res 2002;30:295–300.
[4] Popken G, Wetterauer U, Schultze-Seemann W. Kidney-
preserving tumour resection in renal cell carcinoma
with photodynamic detection by 5-aminolaevulinic
acid: preclinical and preliminary clinical results. BJU
Int 1999;83:578–82.
DOI: 10.1016/j.eururo.2007.11.050
DOI of original article: 10.1016/j.eururo.2007.11.048